Abstract
The tumor microenvironment (TME) includes numerous non-neoplastic cells such as leukocytes and fibroblasts that surround the neoplasm and influence its growth. Tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) are documented as key players in facilitating cancer appearance and progression. Alteration of the macrophage (CD68, CD163) and fibroblast (α-SMA, FSP-1) cells in Opisthorchis viverrini (Ov)-induced cholangiocarcinoma (CCA) was here assessed using liver tissues from an established hamster model and from 43 human cases using immunohistochemistry. We further investigated whether M2-activated TAMs influence CCA cell migration ability by wound healing assay and Western blot analysis. Macrophages and fibroblasts change their phenotypes to M2-TAMs (CD68+, CD163+) and CAFs (α-SMA+, FSP-1+), respectively in the early stages of carcinogenesis. Interestingly, a high density of the M2-TAMs CCA in patients is significantly associated with the presence of extrahepatic metastases (p=0.021). Similarly, CD163+ CCA cells are correlated with metastases (p=0.002), and they may be representative of an epithelial-to-mesenchymal transition (EMT) with increased metastatic activity. We further showed that M2-TAM conditioned medium can induce CCA cell migration as well as increase N-cadherin expression (mesenchymal marker). The present work revealed that significant TME changes occur at an early stage of Ov-induced carcinogenesis and that M2-TAMs are key factors contributing to CCA metastasis, possibly via EMT processes.
Highlights
The tumor microenvironment (TME) is a complex system composed of many cell types as well as non-cellular components (Albini and Sporn, 2007) that coincide with structural support, tissue homeostasis maintenance, and immune surveillance (Shaykhiev and Bals, 2007; Adjei and Blanka, 2015)
The present study takes advantage of an established Opisthorchis viverrini (Ov)-infected animal model and a large series of defined CCA cases to demonstrate for the first time that TME is significantly altered and that this is largely dependent on Tumor-associated macrophages (TAMs) and cancerassociated fibroblasts (CAFs)
We observed that altered macrophages are M2-TAMs which are found at early stages of cholangiocarcinogenesis
Summary
The tumor microenvironment (TME) is a complex system composed of many cell types as well as non-cellular components (Albini and Sporn, 2007) that coincide with structural support, tissue homeostasis maintenance, and immune surveillance (Shaykhiev and Bals, 2007; Adjei and Blanka, 2015). The crosstalk between cancer cells and TME is involved in chronic inflammation leading to cancer progression and metastasis through numerous proteins such as CXCL-12, epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and matrix metalloprotease (MMP) (Joyce and Pollard, 2009; Qian and Pollard, 2010; Rasanen and Vaheri, 2010). These contribute to unsuccessful wound healing that characterizes cancer(Albini and Sporn, 2007). M2 cells are induced by IL-4 and IL-13 (M2a), immune complexes/TLR ligands (M2b), or IL-10 and glucocorticoids (M2c) (Mantovani et al, 2004), which can be defined by several features including high levels of IL-10, IL-1ra, IL-1decoyR and wound-healing promotion
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